Format

Send to

Choose Destination
Kidney Int. 2015 Mar;87(3):543-56. doi: 10.1038/ki.2014.302. Epub 2014 Sep 17.

Phosphorylation of ribosomal protein S6 mediates compensatory renal hypertrophy.

Author information

1
Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.
2
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
3
1] Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA [2] Research Department, Charlie Norwood VA Medical Center, Augusta, Georgia, USA.
4
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
5
1] Department of Cellular Biology and Anatomy, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA [2] Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, USA.

Abstract

The molecular mechanism underlying renal hypertrophy and progressive nephron damage remains poorly understood. Here we generated congenic ribosomal protein S6 (rpS6) knock-in mice expressing nonphosphorylatable rpS6 and found that uninephrectomy-induced renal hypertrophy was significantly blunted in these knock-in mice. Uninephrectomy-induced increases in cyclin D1 and decreases in cyclin E in the remaining kidney were attenuated in the knock-in mice compared with their wild-type littermates. Uninephrectomy induced rpS6 phosphorylation in the wild-type mice; however, no rpS6 phosphorylation was detected in uninephrectomized or sham-operated knock-in mice. Nonetheless, uninephrectomy stimulated comparable 4E-BP1 phosphorylation in both knock-in and wild-type mice, indicating that mTORC1 was still activated in the knock-in mice. Moreover, the mTORC1 inhibitor rapamycin prevented both rpS6 and 4E-BP1 phosphorylation, significantly blunted uninephrectomy-induced renal hypertrophy in wild-type mice, but did not prevent residual renal hypertrophy despite inhibiting 4E-BP1 phosphorylation in uninephrectomized knock-in mice. Thus, both genetic and pharmacological approaches unequivocally demonstrate that phosphorylated rpS6 is a downstream effector of the mTORC1-S6K1 signaling pathway mediating renal hypertrophy. Hence, rpS6 phosphorylation facilitates the increase in cyclin D1 and decrease in cyclin E1 that underlie the hypertrophic nature of uninephrectomy-induced kidney growth.

PMID:
25229342
PMCID:
PMC4344886
DOI:
10.1038/ki.2014.302
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center